Methods and compositions for treating inflammatory response

Abstract

Compositions for oral administration of compounds having A 2A adenosine receptor antagonist activity are provided. These compositions are useful for treatment of inflammatory conditions.

1 - 17 . (canceled)  
     
     
         18 . A method for preparing a compound of the formula (I):  
       
         
           
           
               
               
           
         
         comprising:  
         (i) reacting a compound of formula II with a compound of formula III  
         
           
             
             
                 
                 
             
           
         
         wherein:  
         each R is individually hydrogen, C 1 -C 6  alkyl, C 3 -C 7  cycloalkyl, phenyl or phenyl(C 1 -C 3 )-alkyl;  
         X is —CH 2 OH, —CO 2 R 2 , —OC(O)R 2 , or C(O)NR 3 R 4 ;  
         each of R 2 , R 3  and R 4  is individually H, C 1-6 -alkyl; C 1-6 alkyl substituted with 1-3 C 1-6 alkoxy, C 3 -C 7 cycloalkyl, C 1-6 -alkylthio, halogen, hydroxy, amino, mono-(C 1-6 alkyl)amino, di(C 1-6 alkyl)amino, or C 6-10 -aryl, wherein aryl may be substituted with 1-3 halogen, C 1-6 alkyl, hydroxy, amino, mono(C 1-6 alkyl)amino, or di(C 1-6 alkyl)amino; C 6-10 aryl; or C 6-10 aryl substituted with 1-3 halogen, hydroxy, amino, mono(C 1-6 alkyl)amino, di(C 1-6 alkyl)amino or C 1-6 alkyl;  
         R 1  is (X-(Z)-) n [(C 3 -C 10 )cycloalkyl]-(Z′)- wherein Z and Z′ are individually (C 1 -C 6 )alkyl, optionally interrupted by 1-3 S or nonperoxide O, or are absent, and n is 1-3; or  
         a pharmaceutically acceptable salt thereof.  
       
     
     
         19 . The method of  claim 18 , wherein the compounds of formulas II and III are reacted in the presence of CuI and P(PPh 3 ) 4 .  
     
     
         20 . The method of  claim 18 , wherein 5′-X is CH 2 OH or —C(O)NR 3 R 4 .  
     
     
         21 . The method of  claim 20 , wherein 5′-X is —C(O)NR 3 R 4 .  
     
     
         22 . The method of  claim 21 , wherein R 3  is H and R 4  is (C 1 -C 4 )alkyl.  
     
     
         23 . The method of  claim 18 , wherein each R is H or (C 1 -C 4 )alkyl.  
     
     
         24 . The method of  claim 18 , wherein Z′ is —CH 2 — or —CH 2 —CH 2 —.  
     
     
         25 . The method of  claim 24 , wherein Z is —CH 2 — or —CH 2 —CH 2 —.  
     
     
         26 . The method of  claim 18 , wherein C 3 -C 10  cycloalkyl is cyclohexyl or cyclopentyl.  
     
     
         27 . The method of  claim 26 , wherein X-Z is HO 2 C-Z-.  
     
     
         28 . The method of  claim 26 , wherein X-Z and Z′ are trans on C 3 -C 10  cycloalkyl.  
     
     
         29 . The method of  claim 18 , wherein R is H, and R 1 —C≡C— is 2-(4-methoxycarbonyl-cyclohexylmethyl)ethynyl or 2-(4-carboxy-cyclohexylmethyl)ethynyl.  
     
     
         30 . The method of  claim 18 , wherein R is H, and R 1 —C≡C— is 2-(4-acetoxymethyl-cyclohexylmethyl)ethynyl.